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The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress
Open accessAbstract
The blood system is sustained by a pool of haematopoietic stem cells (HSCs) that are long-lived due to their capacity for self-renewal. A consequence of longevity is exposure to stress stimuli including reactive oxygen species (ROS), nutrient fluctuation and DNA damage. Damage that occurs within stressed HSCs must be tightly controlled to prevent either loss of function or the clonal persistence of oncogenic mutations that increase the risk of leukaemogenesis. Despite the importance of maintaining cell integrity throughout life, how the HSC pool achieves this and how individual HSCs respond to stress remain poorly understood. Many sources of stress cause misfolded protein accumulation in the endoplasmic reticulum (ER), and subsequent activation of the unfolded protein response (UPR) enables the cell to either resolve stress or initiate apoptosis. Here we show that human HSCs are predisposed to apoptosis through strong activation of the PERK branch of the UPR after ER stress, whereas closely related progenitors exhibit an adaptive response leading to their survival. Enhanced ER protein folding by overexpression of the co-chaperone ERDJ4 (also called DNAJB9) increases HSC repopulation capacity in xenograft assays, linking the UPR to HSC function. Because the UPR is a focal point where different sources of stress converge, our study provides a framework for understanding how stress signalling is coordinated within tissue hierarchies and integrated with stemness. Broadly, these findings reveal that the HSC pool maintains clonal integrity by clearance of individual HSCs after stress to prevent propagation of damaged stem cells.
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“Our recent studies have shown that LSCs possess a distinct pro-survival ISR 50 that mirrors that of normal hematopoietic stem cells.55,56”
From CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells (2021) · cites this paper as [56]
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Metadata
- Authors
- van Galen, P., Kreso, A., Mbong, N., Kent, D. G., Fitzmaurice, T., Chambers, J. E., Xie, S., Laurenti, E., Hermans, K., Eppert, K., Marciniak, S. J., Goodall, J. C., Green, A. R., Wouters, B. G., Wienholds, E., & Dick, J. E.
- Affiliations
- University Health Network (CA)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- McGill University Health Centre (CA)
- University of Cambridge (GB)
- Corresponding author
- Dick, John E.
- ORCID
- Venue
- Nature
- Published
- 2014-04-28
- Volume
- 510
- Issue
- 7504
- Pages
- 268-272
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1999203943
- Cited by
- 363
- References
- 40
- Citations by year
- 2026: 11 · 2025: 31 · 2024: 23 · 2023: 28 · 2022: 27 · 2021: 24 · 2020: 51 · 2019: 34 · 2018: 32 · 2017: 33 · 2016: 22 · 2015: 34 · 2014: 12
- FWCI
- 23.87
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (100140, 100140/Z/12/Z)
- Cancer Research UK
- Hospital for Sick Children
- Versus Arthritis (19639)
- Canadian Institutes of Health Research (201592)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- hematopoietic stem cells, unfolded protein response, endoplasmic reticulum stress, PERK pathway, apoptosis, DNAJB9, stemness, leukemogenesis, HSC transplantation
- MeSH terms
- Animals, Hematopoietic Stem Cells, Humans, Male, Membrane Proteins, Tunicamycin, Signal Transduction, Eukaryotic Initiation Factor-2, Apoptosis, Protein Folding, Molecular Chaperones, eIF-2 Kinase, HSP40 Heat-Shock Proteins, Mice, Activating Transcription Factor 4, Transcription Factor CHOP, Protein Phosphatase 1, Unfolded Protein Response, Endoplasmic Reticulum Stress, Heterografts
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